Brain serotonin system plays a critical role in numerous neuronal functions and dysregulation of its homeostasis may contribute to many psychiatric disorders (Veenestra-VanderWeele et al, 2000; Flattem and Blakely 2000; Blier and Abbott 2001; Tecott, 2003; Geyer, 1996; Tamminga, 1998; Snyder and Peroutka, 1982; Frazer, 1997; Aghajanian and Marek, 2000). In fact, numerous conditions such as unipolar major depression and bipolar disorder, obsessive-compulsive disorder, anxiety, autism, personality disorder, panic and eating disorders, suicidality, chronic pain and post-traumatic stress syndrome and even attention deficit hyperactivity disorder (ADHD), are effectively treated by raising the extracellular concentrations of serotonin in the brain with compounds including selective serotonin reuptake inhibitors (SSRIs) that inhibit the neuronal re-uptake of serotonin. Like many other neurotransmitters and modulators, the actions of serotonin are modulated by the delicate balance between synthesis and degradation of this monoamine. Tryptophan hydroxylase-1 (Tph1) has long been considered as the sole rate-limiting enzyme for the synthesis of serotonin. However, Walther et al (2003) recently reported that inactivation of the Tph1 gene in the mouse led to a decrease in the peripheral levels of serotonin but no changes in central serotonin levels, suggesting that another form of the enzyme might exist. Data base mining yielded a second related gene that was identified, cloned and named TPH2. The product of the TPH2 gene is preferentially expressed in the brain as opposed to the predominant peripheral expression pattern of TPH1 (Walther et al, 2003).
M. Bader et al., PCT Application WO 2004/007704 (US 2006/0275759), describes the identification of TPH2.